P2X4 purinoceptor signaling in chronic pain

Trang, Tuan; Salter, Michael W.

doi:10.1007/s11302-012-9306-7

Cited by 56 publications

(54 citation statements)

References 90 publications

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“…Amongst the plethora of well-described subsets of immune receptors a growing body of evidence now points to purinergic receptors on microglia as contributing to various neuropathologies 52, 53 . Notably, ionotropic P2X receptor subtype P2X4R has emerged as a key regulator of microglial functions and has been implicated in neurodegenerative and neuroimmune disorders 45 .…”

Section: Discussionmentioning

confidence: 99%

P2X4 Receptor Regulates Alcohol-Induced Responses in Microglia

Gofman

Cenna

Potula

2014

J Neuroimmune Pharmacol

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Mounting evidence indicates that alcohol-induced neuropathology may result from multicellular responses in which microglia cells play a prominent role. Purinergic receptor signaling plays a key role in regulating microglial function and, more importantly, mediates alcohol-induced effects. Our findings demonstrate that alcohol increases expression of P2X4 receptor (P2X4R), which alters the function of microglia, including calcium mobilization, migration and phagocytosis. Our results show a significant up-regulation of P2X4 gene expression as analyzed by real-time qPCR (***p<0.002) and protein expression as analyzed by flow cytometry (**p<0.004) in embryonic stem cell-derived microglial cells (ESdM) after 48 hours of alcohol treatment, as compared to untreated controls. Calcium mobilization in ethanol treated ESdM cells was found to be P2X4R dependent using 5-BDBD, a P2X4R selective antagonist. Alcohol decreased migration of microglia towards fractalkine (CX3CL1) by 75% following 48 hours of treatment compared to control (***p<0.001). CX3CL1-dependent migration was confirmed to be P2X4 receptor-dependent using the antagonist 5-BDBD, which reversed the effects as compared to alcohol alone (***p<0.001). Similarly, 48 hours of alcohol treatment significantly decreased phagocytosis of microglia by 15% compared to control (*p<0.05). 5-BDBD pre-treatment prior to alcohol treatment significantly increased microglial phagocytosis (***p<0.001). Blocking P2X4R signaling with 5-BDBD decreased the level of calcium mobilization compared to ethanol treatment alone. These findings demonstrate that P2X4 receptor may play a role in modulating microglial function in the context of alcohol abuse.

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Section: Discussionmentioning

confidence: 99%

P2X4 Receptor Regulates Alcohol-Induced Responses in Microglia

Gofman

Cenna

Potula

2014

J Neuroimmune Pharmacol

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“…Over 80% of rat lumbar DRG neurons express P2X4, half of which also co-express the TrkA receptor [19]. Although much research has focused on the role for glial P2X4 receptors in pain mechanisms, this widespread expression of P2X4 in nociceptive DRG neurons suggests that neuronal P2X4 receptors may also play a role in pain [29]. …”

Section: Discussionmentioning

confidence: 99%

Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity

Barr¹,

Hrnjic²,

Khodorova³

et al. 2014

Pain

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Endothelin (ET-1), an endogenous peptide with a prominent role in cutaneous pain, causes mechanical hypersensitivity in the rat hind paw, partly through mechanisms involving local release of algogenic molecules in the skin. The present study investigated involvement of cutaneous ATP, which contributes to pain in numerous animal models. Pre-exposure of ND7/104 immortalized sensory neurons to ET-1 (30 nM) for 10 min increased the proportion of cells responding to ATP (2 μM) with an increase in intracellular calcium, an effect prevented by the ETA receptor-selective antagonist BQ-123. ET-1 (3 nM) pre-exposure also increased the proportion of isolated mouse DRG neurons responding to ATP (0.2-0.4 μM). Blocking ET-1-evoked increases in intracellular calcium with the IP3 receptor antagonist 2-APB did not inhibit sensitization to ATP, indicating a mechanism independent of ET-1-mediated intracellular calcium increases. ET-1-sensitized ATP calcium responses were largely abolished in the absence of extracellular calcium, implicating ionotropic P2X receptors. Experiments using qPCR and receptor-selective ligands in ND7/104 showed that ET-1-induced sensitization most likely involves the P2X4 receptor subtype. ET-1-sensitized calcium responses to ATP were strongly inhibited by broad spectrum (TNP-ATP) and P2X4-selective (5-BDBD) antagonists, but not antagonists for other P2X subtypes. TNP-ATP and 5-BDBD also significantly inhibited ET-1-induced mechanical sensitization in the rat hind paw, supporting a role for purinergic receptor sensitization in vivo. These data provide evidence that mechanical hypersensitivity caused by cutaneous ET-1 involves an increase in the neuronal sensitivity to ATP in the skin, possibly due to sensitization of P2X4 receptors.

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“…86,87 Kazu Inoue and colleagues showed that there was increased expression of P2X4 receptors on microglia in neuropathic pain, and this pain was reduced by antagonists to the P2X4 receptor and in P2X4 receptor knockout mice. 88,89 Later, antagonists to P2X7 and P2Y receptors expressed on microglia were also shown to reduce neuropathic pain. 86 P2X3 and P2X7 receptors are being targeted for the treatment of arthritis.…”

Section: Painmentioning

confidence: 99%

Purinergic Signalling: Pathophysiology and Therapeutic Potential

Burnstock

2013

Keio J. Med.

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The article begins with a review of the main conceptual steps involved in the development of our understanding of purinergic signalling, including non-adrenergic, non-cholinergic (NANC) neurotransmission; identification of ATP as a NANC transmitter; purinergic cotransmission; recognition of two families of purinoceptors [P1 (adenosine) and P2 (ATP/ADP)]; and, later, cloning and characterisation of P1 (G protein-coupled), P2X (ion channel) and P2Y (G protein-coupled) receptor subtypes. Further studies have established the involvement of ATP in synaptic neurotransmission in both ganglia and in the central nervous system; long-term (trophic) purinergic signalling in cell proliferation, differentiation and death occurring in development and regeneration; and short-term purinergic signalling in neurotransmission, neuromodulation and secretion. ATP is released from most cell types in response to gentle mechanical stimulation and is rapidly degraded to adenosine by ecto-nucleotidases. This review then focuses on the pathophysiology of purinergic signalling in a wide variety of systems, including urinogenital, cardiovascular, airway, musculoskeletal and gastrointestinal. Consideration is also given to the involvement of purinoceptors in pain, cancer and diseases of the central nervous system. Purinergic therapeutic approaches for the treatment of some of these diseases are discussed.

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P2X4 purinoceptor signaling in chronic pain

Cited by 56 publications

References 90 publications

P2X4 Receptor Regulates Alcohol-Induced Responses in Microglia

P2X4 Receptor Regulates Alcohol-Induced Responses in Microglia

Sensitization of cutaneous neuronal purinergic receptors contributes to endothelin-1-induced mechanical hypersensitivity

Purinergic Signalling: Pathophysiology and Therapeutic Potential

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